The purpose of the proposed research is to develop methods to treat infants and children who have defects of each of the five enzymes required for urea synthesis. Two approaches to achieve this goal will be used: (1) to find alternative pathways of waste nitrogen excretion either as urea cycle intermediates or as amino acid acylation products; (2) to minimize the requirements for waste nitrogen excretion by supplementing a low protein diet with the nitrogen-free analogues of essential amino acids. Other aspects of this proposal include a study of the physiological consequence of (1) accelerated pyrimidine synthesis, (2) heterozygosity for ornithine transcarbamylase deficiency, (3) transient asymptomatic hyperammonemia of low birth weight infants, and (4) arginine deficiency. Infants with partial or complete deficiency of carbamyl phosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase, identified here or elsewhere, will be maintained on a low-protein regimen in which essential amino acid requirements are met by a mixture of nitrogen-free analogues of essential amino acids and essential and essential amino acids as such, produced at Johns Hopkins. Dosage of individual components and protein intake will be modified continually so as to optimize physical growth, neurodevelopment, and biochemical parameters. Residual urea synthetic capacity will be determined in each infant using N-15 labelled amino acids. Children who can be maintained in a stable condition using these dietary supplements will be brought to Johns Hopkins for study of enhanced waste nitrogen using sodium benzoate, sodium phenylacetate, homocitrulline and homoarginine. Premature infants will be studied in terms of physical and mental development, habituation, discrimination and attention while hyperammonemia is controlled by dietary means.